Pharmaceutical Composition Containing Prostaglandin

ABSTRACT

An object of the present invention is to provide a stable aqueous pharmaceutical composition which suppresses degradation of prostaglandin F 2α  in a preparation containing prostaglandin F 2α . The object was attained by formulating a prostaglandin F 2α  derivative into an oil-in-water emulsion together with an oil, for example, medium chain fatty acid triglyceride, a water-soluble polymer and water.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition which isan oil-in-water emulsion comprising a prostaglandin F_(2α), derivative,an oil, a water-soluble polymer and water, as well as a method ofsuppressing degradation of prostaglandin F_(2α), in the composition.

BACKGROUND ART

Prostaglandin is a physiologically active substance derived from apolyunsaturated fatty acid, and has various important pharmacologicaland physiological actions at a very small amount, and therefore, variousderivatives thereof have been synthesized and developed for medicine.For example, derivatives of prostaglandin F_(2α), are useful as amedicament for treating glaucoma or ocular hypertension, and some eyedrops have already been developed and marketed. However, in order toprepare an aqueous preparation of a derivative of prostaglandin, weshould overcome some problems that prostaglandin and a derivativethereof are poorly soluble in water and, when dissolved in water, theyare easily degraded, and further a content of prostaglandin and itsderivative is reduced due to adsorption onto a container.

So far, as an aqueous liquid preparation of prostaglandin or aderivative thereof, for example, a composition obtained by solubilizingand stabilizing prostaglandin by formation of a complex with etherizedcyclodextrin (see Patent Document 1), a fat emulsion of a stable PGE₁analogue (see Patent Document 2), a prostaglandin composition containinga polyethoxylated castor oil (see Patent Document 3), a prostaglandinfat emulsion containing an purified olive oil, phospholipid and water,which can be intravenously administered (see Patent Document 4), and aneye drop containing a prostaglandin derivative in which a nonionicsurfactant and/or an antioxidant is blended (see Patent Document 5) aredisclosed.

Patent Document 1: Japanese Patent Application Laid-Open (JP-A) No.H01-221317 (corresponding to EP330511)

Patent Document 2: JP-A No. H07-10833

Patent Document 3: JP-A No. H11-500122 (corresponding to WO97/029752)

Patent Document 4: JP-A No. 2001-10958

Patent Document 5: JP-A No. 2002-161037 (corresponding to EP1321144)

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a new aqueouspharmaceutical composition in which degradation of a prostaglandinF_(2α) derivative is suppressed.

Means for Solving Problems

The present inventors have studied to seek a dosage form which canprevent degradation of a prostaglandin F_(2α), derivative in an aqueouspharmaceutical composition containing a prostaglandin F_(2α) derivative.As a result, they have found out that an oil-in-water emulsion obtainedby blending an oil, inter alia, medium chain fatty acid triglyceride anda water-soluble polymer can provide a pharmaceutical composition inwhich degradation of a prostaglandin F_(2α) derivative is remarkablysuppressed, and have completed the present invention.

That is, the present invention provides the following inventions:

(1) a pharmaceutical composition comprising an oil-in-water emulsioncontaining a prostaglandin F_(2α) derivative, an oil, a water-solublepolymer and water,(2) the pharmaceutical composition according to (1), wherein theprostaglandin F_(2α), derivative is at least one member selected fromlatanoprost, isopropyl unoprostone, travoprost and bimatoprost,(3) the pharmaceutical composition according to (2), wherein theprostaglandin F_(2α) derivative is latanoprost,(4) the pharmaceutical composition according to (1), wherein thewater-soluble polymer is at least one member selected from a polyvinylcompound, a water-soluble cellulose compound and a polysaccharide,(5) the pharmaceutical composition according to (4), wherein thepolyvinyl compound is polyvinyl alcohol,(6) the pharmaceutical composition according to (1), wherein the oil isan animal or vegetable oil and/or medium chain fatty acid triglyceride,(7) the pharmaceutical composition according to (6), wherein the mediumchain fatty acid triglyceride is Miglyol,(8) the pharmaceutical composition according to any one of (1) to (7),wherein the pharmaceutical composition is an opthalmologicalcomposition,(9) the pharmaceutical composition according to (8), wherein theopthalmological composition is an eye drop,(10) an eye drop which is an oil-in-water emulsion, comprisinglatanoprost, Miglyol, polyvinyl alcohol and water,(11) a method of suppressing degradation of a prostaglandin F_(2α),derivative in an emulsion, comprising blending a prostaglandin F_(2α)derivative, an oil, a water-soluble polymer and water to form anoil-in-water emulsion, and(12) a method of suppressing degradation of latanoprost in an emulsion,comprising blending latanoprost, miglyol, polyvinyl alcohol and water toform an oil-in-water emulsion.

Effect of the Invention

According to the present invention, degradation of prostaglandin F_(2α)can be remarkably suppressed. Therefore, a stable pharmaceuticalcomposition incorporating prostaglandin F_(2α) can be prepared, andsubjected to use.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be explained in more detail.

The pharmaceutical composition of the present invention is anoil-in-water emulsion containing an oil, a water-soluble polymer andwater together with a prostaglandin F_(2α) derivative. By adopting sucha dosage form, degradation of a prostaglandin F_(2α), derivative can beremarkably suppressed.

Prostaglandin F_(2α) derivative used in the present invention includes apharmaceutically acceptable salt and ester thereof. Examples of thepharmaceutically acceptable salt include salts with an organic base e.g.an alkali metal such as sodium and potassium, an alkaline earth metalsuch as calcium and magnesium, and an ammonium salt, and salts with aninorganic acid such as hydrochloric acid and phosphoric acid, and anorganic acid such as acetic acid, citric acid, and succinic acid.Examples of the pharmaceutically acceptable ester include esters oflower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl and hexyl.

Examples of the prostaglandin F_(2α) derivative to be blended in thepharmaceutical composition of the present invention include latanoprost,isopropyl unoprostone, travoprost, and bimatoprost, and compoundsdescribed in JP-A No. 2002-161037 (aforementioned Patent Document 5)and, inter alia, latanoprost is preferable. The prostaglandin F_(2α)derivative can be blended in the pharmaceutical composition of thepresent invention at a lower limit of about 0.0001 (W/V) %, preferablyabout 0.001 (W/V) %, and an upper limit of about 0.4 (W/V) %, preferablyabout 0.05 (W/V) %.

The oil used in the present invention is not particularly limited, butmedium chain fatty acid triglyceride, or an animal oil or vegetable oilcontaining fatty acid triglyceride as a main component, or both of themmay be used. Among them, medium chain fatty acid triglyceride is morepreferable. Medium chain fatty acid triglyceride refers to saturatedfatty acid triglyceride of the carbon number of 4 to 12, or a mixturethereof a majority of which consists of fatty acid triglyceride havingsuch carbon numbers. Practically, a product containing fatty acidtriglyceride of the carbon number of 8 (caprylic acid) or 10 (capricacid) as a main component obtained by hydrolyzing a palm oil, or a palmkernel oil once, purifying, and combining again can be used. Examples ofthe products (trade names) include Miglyol (Mitsuba Boeki), Coconade(Kao), ODO (Nisshin Oillio), Panasate (Nippon Oil & Fats Co., Ltd.),TCG-M (Higher Alcohol Industry), and Actor (Riken Vitamin) and, interalia, Miglyol is preferable. Among Miglyol, Miglyol 812 and 810 areparticularly preferable. Examples of the animal or vegetable oil includea castor oil, a soybean oil, a peanut oil, a cottonseed oil, an oliveoil, a sesame oil, a camellia oil, a sunflower oil, a coconut oil, apalm oil, a palm kernel oil, a peanut oil, a tung oil, a rapeseed oil, acorn oil, beef tallow, and lard containing triglyceride of fatty acidhaving the carbon number of 4 to 24 such as butyric acid, caproic acid,caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid,stearic acid, arachic acid, behenic acid, lignoceric acid, palmitoleicacid, oleic acid, linoleic acid, linolenic acid, and ricinoleic acid.These oils can be used alone, or in combination with two or moreappropriately.

An amount of the oil to be blended in the pharmaceutical composition ofthe present invention may be appropriately determined depending on anamount of a prostaglandin F_(2α) derivative as far as an oil-in-wateremulsion is formed, and a lower limit is about 0.005 W/V %, preferablyabout 0.1 W/V %, and an upper limit is about 20 W/V %, preferably about5 W/V %.

In the pharmaceutical composition of the present invention, awater-soluble polymer is used as an emulsifier. In addition to thiswater-soluble polymer, as an emulsifier, the composition may beappropriately used by combining with phospholipid such as yolk lecithin,or a surfactant.

Water-solubility in the water-soluble polymer means that 1 g or more ofthe polymer compound can be dissolver in 100 g of water at 20° C.Examples of the water-soluble polymer include water-soluble cellulosecompounds such as methylcellulose, hydroxyethylcellulose,hydroxypropylmethyl-cellulose and sodium cellulose, polyvinyl compoundssuch as polyvinyl alcohol, and polyvinylpyrrolidone, and polysaccharidessuch as alginic acid, xanthan gum, carrageenan, and chitosan, preferablypolyvinyl alcohol and hydroxypropylmethylcellulose, most preferablypolyvinyl alcohol. As the polyvinyl alcohol, both of a partiallysaponified entity and a completely saponified entity can be used. Thesewater-soluble polymer compounds can be used alone, or in combinationwith two or more of them appropriately.

An amount of the water-soluble polymer to be blended in thepharmaceutical composition of the present invention may be appropriatelydetermined depending on an amount of the oil to be blended as far as anoil-in-water emulsion is formed, and a lower limit is about 0.001 (W/V)%, preferably about 0.1 (W/V) %, and an upper limit is about 20 (W/V) %,preferably about 5 (W/V) %.

Further, various additives such as buffers, isotonics, preservatives,solubilizers, stabilizers, chelating agents, thickeners, and pHadjusting agents may be appropriately blended in the pharmaceuticalcomposition of the present invention.

Examples of buffers include boric acid or a salt thereof (borax etc.),citric acid or a salt thereof (sodium citrate etc.), tartaric acid or asalt thereof (sodium tartrate etc.), gluconic acid or a salt thereof(sodium gluconate etc.), acetic acid or a salt thereof (sodium acetateetc.), phosphoric or a salt thereof (sodium monohydrogen phosphate,sodium dihydrogen phosphate etc.), various amino acids such as glutamicacid and epsilonaminocaproic acid, and Tris buffers, and a combinationthereof.

Examples of the isotonics include sorbitol, glucose, mannitol, glycerin,propylene glycol, sodium chloride, and potassium chloride.

Examples of the preservatives include p-oxybenzoic acid esters,benzalkonium chloride, benzethonium chloride, benzyl alcohol, sorbicacid or a salt thereof, chlorhexidine gluconate, sodium dehydroacetate,cetylpyridinium chloride, alkyldiaminoethylglycine hydrochloride, andchlorobutanol.

Examples of the solubilizers include polyvinylpyrrolidone, polyethyleneglycol, propylene glycol, polyoxyethylene hydrogenated castor oil 60,and stearic acid polyoxyl 40.

Examples of the stabilizers include sodium edetate, sodium thiosulfate,ascorbic acid, cyclodextrin, condensed phosphoric acid or a saltthereof, sulfite, citric acid or a salt thereof, anddibutylhydroxytoluene, and the like.

Examples of the chelating agents include sodium edetate, sodium citrate,and condensed phosphoric acid or a salt thereof (sodium condensedphosphate), and the like.

Examples of the thickeners include methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, sodium chondroitin sulfate, sodiumcarboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, andpolyethylene glycol, etc.

Examples of the pH adjusting agents include sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium bicarbonate, boric acid or a saltthereof (borax), hydrochloric acid, citric acid or a salt thereof(sodium citrate, sodium dihydrogen citrate etc.), phosphoric acid or asalt thereof (disodium hydrogen phosphate, potassium dihydrogenphosphate etc.), acetic acid or a salt thereof (sodium acetate, ammoniumacetate etc.), and tartaric acid or a salt thereof (sodium tartrateetc.), and the like.

A median diameter of oil particles of the pharmaceutical composition ofthe present invention is preferable 0.0001 to 5 μm, more preferably0.001 to 1 μm, particularly preferably 0.01 to 1 μm. A median diametercan be measured using a particle size distribution measuring apparatus.

A pH of the pharmaceutical composition of the present invention isadjusted to 3 to 10, preferably 5 to 8.

The pharmaceutical composition of the present invention can besystemically administered in an injectable dosage form and also, can beused as an opthalmological composition such as an eye drop which islocally administered. Since degradation of a prostaglandin F_(2α)derivative is remarkably suppressed, the pharmaceutical composition ofthe present invention is useful, particularly, for an eye drop which isusually continued to be used for a certain period of term after breakingthe seal.

The prostaglandin F_(2α) derivative-containing pharmaceuticalcomposition of the present invention can be provided by a conventionalmethod for preparing an oil-in-water emulsion. As a preferable method,the following can be exemplified. That is, the composition is preparedby adding an emulsifier and, if necessary, the aforementioned additivesto water, adding an oil in which a prostaglandin F_(2α), derivative isdissolved to obtain an emulsion, and adjusting a pH to 3 to 10 using apH adjusting agent. For performing emulsification uniformly, thepublicly known means such as a mixer, a homogenizer, a homomixer, amicrofluidizer, and a high-pressure homogenizer can be used.

EXAMPLES

The present inventions will be explained more specifically below by wayof Test Examples and Preparation Examples, but these are merelyexemplary, and the present inventions are not limited by them.

Test Example 1 Stability of Latanoprost in Oil Test Method

As oils, an olive oil, a cottonseed oil, a peanut oil, a rapeseed oil, asoybean oil, a tung oil and Miglyol 812 were used. Five milligram oflatanoprost(isopropyl-(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptanoate) was weighed, and each 1000 mg of each oil was added tolatanoprost. The mixture was stirred for 30 minutes with a magneticstirrer so that latanoprost was dissolved to prepare about 1000 mg of alatanoprost oil solution (5 mg/g). After dissolution was observed withnaked eyes, a latanoprost oil solution was sampled, and a latanoprostcontent was measured by a HPLC method (day 0). Each 500 μL of theselatanoprost oil solutions was dispensed in a glass sample bottle, andwas stored at 60° C. or 80° C. for 7 days. On seventh day, sampling wasperformed, a latanoprost content was measured, and a remaining rate wascalculated from a ratio relative to a value measured on 0 day. Eachsampling was performed by weighing a constant amount of a latanoprostoil solution, and diluted with tetrahydrofuran and the following mobilephase A, and was supplied for measurement of HPLC.

HPLC analysis conditions: a Waters Extera RP₁₈, 5 μm, φ 4.6×150 mmcolumn was used. As a mobile phase A, a mixture of acetonitrile: 10 mMsodium 1-octanesulfonate aqueous solution (pH 3.5)=35:65 was used, andas a mobile phase B, a mixture of acetonitrile: 10 mM sodium1-octanesulfonate aqueous solution (pH 3.5)=10:90 was used. A volume ofinjection was 50 μL and, a ultraviolet spectrophotometer (measuringwavelength: 210 nm) was used as a detector. A column temperature waskept at around 25° C. Analysis was performed by flowing the mobile phaseA for 30 minutes and, thereafter, flowing the mobile phase B for 5minutes for column washing, and the mobile phase A for 7 minutes forequilibration. A flow rate of the mobile phase was 1.5 mL/min.

Test Results

A latanoprost remaining rate (%) in each oil is shown in Table 1.

TABLE 1 Latanoprost remaining rate (%) in oil 7 days 60° C. 80° C. Oliveoil 103.6 78.4 Cottonseed oil 105.9 67.3 Peanut oil 103.9 90.2 Rapeseedoil 104.2 70.5 Soybean oil 111.1 82.4 Tung oil 93.3 42.7 Miglyol 812105.5 104.4

Apparent from these test results, latanoprost dissolved in the oil wasstable at 60° C. in most of oils although it was warmed. At 80° C.,latanoprost was particularly stable in Miglyol 812.

Test Example 2 Stability of Latanoprost-Containing Oil-in-Water EmulsionTest Method

Into the mixture of 0.01 g of latanoprost, 2.0 g of Miglyol 812, 4.0 gof Gosenol EG05 (Trade name, partially saponified polyvinyl alcohol, TheNippon Synthetic Chemical Industry Co., Ltd.), 5.2 g of concentratedglycerin (Glycerin content: 98 wt % or more), an appropriate amount ofpurified water was added to make 100 mL in total.

That is, first, a part of purified water was warmed to about at 70° C.,Gosenol and concentrated glycerin were added to dissolve them andobtained an aqueous solution. Separately, latanoprost was a dissolved inMiglyol 812 to prepare an oily solution. Then, the oily solution wasgradually added to the aqueous solution while being stirred with ahomomixer (ROBO MICS, Tokyo Tokushu Kika Kogyo Co., Ltd.), to performrough emulsification (8000 rpm, 15 min), and sterile purified water wasadded to the rough emulsion to make a predetermined amount of theemulsion. This rough emulsion was finely-emulsified (1500 kgf/cm², 10pass) with a microfluidizer (M−110EH, Microfluidics Corporation) toobtain a 0.01% latanoprost emulsion (a stock liquid).

This 0.01% latanoprost emulsion was diluted about two times with thefollowing buffers having a pH of 5, 6 or 7, respectively. The pHs of therespective emulsions were adjusted to the same pHs as those of theoriginal buffers with NaOH and/or HCl. Thus, six kinds of emulsions oflatanoprost having the final concentration of 0.005% (Formulations 1 to6) were prepared.

Formulation 1: 0.3% ε-aminocaproic acid buffer (pH 5) Formulation 2:0.2% sodium acetate buffer (pH 5) Formulation 3: 0.2% sodium acetatebuffer (pH 6) Formulation 4: 0.2% phosphate buffer (pH 6) Formulation 5:0.2% phosphate buffer (pH 7) Formulation 6: 0.2% borate buffer (pH 7)

Each 2 mL of each formulation was filled into a 2 mL brown glassampoule, and stored at 4° C. or 60° C. for 4 weeks under lightshielding. The stored sample was sampled every week, and latanoprostcontent was measured by a HPLC method under the same condition as thatof Test Example 1. Each sample was subjected to measurement as it waswithout dilution. As a comparison control formation, Xalatan eye drop(trade name, containing 0.005% latanoprost, pH 6.5 to 6.9, manufacturedby Pharmacia, Lot No. PT480) was stored under the same storingconditions, and latanoprost content was measured.

Test Results

Latanoprost remaining rate in each formulation: %=(remaining amount at60° C./remaining amount at 4° C.)×100 is shown in Table 2.

TABLE 2 Latanoprost remaining rate (%) in formulation 1 week 2 weeks 3weeks 4 weeks Formulation 1 97.8 100.6 99.5 98.3 Formulation 2 103.599.4 99.7 100.4 Formulation 3 99.3 98.9 99.1 100.7 Formulation 4 100.399.4 96.8 98.2 Formulation 5 99.9 93.9 98.7 102.8 Formulation 6 99.0101.1 100.3 99.2 Xalatan 94.4 94.2 86.5 76.4

All latanoprost remaining rates in formulations 1 to 6 which had beenstored at 60° C. for 4 weeks were higher than that of Xalatan, and itwas shown that latanoprost is stable in these formulations.

As apparent from the above test results, it was recognized that anoil-in-water emulsion formulating latanoprost together with a mediumchain fatty acid triglyceride and a water-soluble polymer remarkablysuppressed the degradation of latanoprost.

Preparation Examples of the prostaglandin F_(2α) derivative-containingoil-in-water emulsion of the present invention will be shown below.

Preparation Example 1 Eye Drop

Latanoprost 0.01 g Concentrated glycerin 2.4 g Polyvinyl alcohol 2 gSodium acetate 0.1 g Sodium edetate 0.01 g Chlorhexidine gluconatesolution (20 W/V %) 0.025 mL Miglyol 812 1 g Hydrochloric acid q.s.Purified water ad 100 mL pH 7.0

According to the above formulation, concentrated glycerin and polyvinylalcohol were dispersed in an aqueous sodium acetate solution, thedispersion was warmed and dissolved while vigorously stirring with ahomomixer, and Miglyol in which latanoprost had been dissolved was addedto prepare an emulsion. The emulsion was cooled to room temperature,sodium edetate, and a chlorhexidine gluconate solution were added, 1Nhydrochloric acid was added to adjust a pH. After the addition ofpurified water to make a predetermined volume, the emulsion wassterilized by filtration to prepare an eye drop.

Preparation Example 2 Eye Drop

Latanoprost 0.005 g Concentrated glycerin 2.4 g Boric acid 1.6 g Sodiumedetate 0.01 g Sorbic acid 0.2 g Hydroxypropylmethylcellulose 0.9 gMiglyol 812 0.6 g Hydrochloric acid q.s. Purified water ad 100 mL pH 7.0

According to the above formulation, concentrated glycerin andhydroxypropylmethylcellulose were gradually dispersed in an aqueousboric acid solution, the dispersion was warmed and dissolved whilevigorously stirring with a homomixer, and Miglyol in which latanoprosthad been dissolved was further added to prepare an emulsion. Theemulsion was cooled to room temperature, sodium edetate and sorbic acidwere added, hydrochloric acid was added to adjust a pH. After theaddition of purified water to make a predetermined volume, the emulsionwas sterilized by filtration to prepare an eye drop.

Preparation Example 3 Eye Drop

Latanoprost 0.005 g Concentrated glycerin 2.4 g Sodium acetate 0.1 gSodium edetate 0.01 g Sorbic acid 0.2 g Xanthan gum 0.9 g Peanut oil 0.6g Hydrochloric acid q.s. Purified water ad 100 mL pH 6.0

According to the above formulation, concentrated glycerin and xanthangum were gradually dispersed in an aqueous sodium acetate solution, thedispersion was warmed and dissolved while vigorously stirring with ahomomixer, and a peanut oil in which latanoprost had been dissolved wasfurther added to prepare an emulsion. The emulsion was cooled to roomtemperature, sodium edetate and sorbic acid were added, 1N hydrochloricacid was added to adjust a pH. After the addition of purified water tomake a predetermined volume, the emulsion was sterilized by filtrationto prepare an eye drop.

Preparation Example 4

Isopropyl unoprostone 0.12 g Concentrated glycerin 2.4 g Polyvinylalcohol 2.0 g Sodium acetate 0.1 g Sodium edetate 0.01 g Chlorhexidinegluconate solution 20 (W/V %) 0.025 mL Miglyol 812 1.0 g Hydrochloricacid q.s. Purified water ad 100 mL pH 6.0

According to the above formulation, concentrated glycerin and polyvinylalcohol were dispersed in an aqueous sodium acetate solution, thedispersion was warmed and dissolved while vigorously stirring with ahomomixer. Miglyol in which isopropyl unoprostone had been dissolved wasfurther added to prepare an emulsion. The emulsion was cooled to roomtemperature, and sodium edetate, and a chlorhexidine gluconate solutionwere added. 1N hydrochloric acid was added to adjust a pH and purifiedwater was added to make a predetermined volume, the emulsion wassterilized by filtration to prepare an eye drop.

Preparation Example 5

Isopropylunoprostone 0.12 g Concentrated glycerin 2.4 g Polyvinylalcohol 2.0 g Polysorbate 80 2.0 g Sodium acetate 0.1 g Sodium edetate0.01 g Sorbic acid 0.2 g Miglyol 812 5.0 g Hydrochloric acid q.s.Purified water ad. 100 mL PH 6.5

According to the above formulation, concentrated glycerin, Polysorbate80 and polyvinyl alcohol were dispersed in an aqueous sodium acetatesolution, and the dispersion was warmed and dissolved while vigorouslystirring with a homomixer. Isopropyl unoprostone dissolved in Miglyolwas further added to prepare an emulsion. The emulsion was cooled toroom temperature, and sodium edetate and sorbic acid were added. 1Nhydrochloric acid was added to adjust a pH, and the emulsion wasmeasured up, and sterilized by filtration to prepare an eye drop.

INDUSTRIAL APPLICABILITY

The present invention can provide a stable pharmaceutical compositioncontaining a prostaglandin F_(2α) derivative, for example, an eye dropwhich is applied to glaucoma or high ocular tension.

1. A pharmaceutical composition comprising an oil-in-water emulsioncontaining a prostaglandin F_(2α) derivative, an oil, a water-solublepolymer and water.
 2. The pharmaceutical composition according to claim1, wherein the prostaglandin F_(2α) derivative is at least one memberselected from latanoprost, isopropyl unoprostone, travoprost andbimatoprost.
 3. The pharmaceutical composition according to claim 2,wherein the prostaglandin F_(2α) derivative is latanoprost.
 4. Thepharmaceutical composition according to claim 1, wherein thewater-soluble polymer is at least one member selected from a polyvinylcompound, a water-soluble cellulose compound and a polysaccharide. 5.The pharmaceutical composition according to claim 4, wherein thepolyvinyl compound is polyvinyl alcohol.
 6. The pharmaceuticalcomposition according to claim 1, wherein the oil is an animal orvegetable oil, and/or medium chain fatty acid triglyceride.
 7. Thepharmaceutical composition according to claim 6, wherein the mediumchain fatty acid triglyceride is Miglyol.
 8. The pharmaceuticalcomposition according to any one of claims 1 to 7, wherein thepharmaceutical composition is an opthalmological composition.
 9. Thepharmaceutical composition according to claim 8, wherein theopthalmological composition is an eye drop.
 10. An eye drop which is anoil-in-water emulsion, comprising latanoprost, Miglyol, polyvinylalcohol and water.
 11. A method of suppressing degradation of aprostaglandin F_(2α) derivative in an emulsion, comprising blending aprostaglandin F_(2α) derivative, an oil, a water-soluble polymer andwater to form an oil-in-water emulsion.
 12. A method of suppressingdegradation of latanoprost in an emulsion, comprising blendinglatanoprost, Miglyol, polyvinyl alcohol and water to form anoil-in-water emulsion.